臺灣博碩士論文加值系統

治療敗血症病人是一項具挑戰性工作，因為一方面要處理周邊血管阻力下降所引起的低血壓，另一方面要接受類交感神經升壓藥物很快會在病人身上產生耐受性的事實，因此頑固性低血壓仍然是造成敗血症高死亡率及傷殘率的主要原因。在生理狀態下，神經性血管運動張力是維持正常血壓的主要因素，所以在敗血症狀態下，對調節神經性血管運動張力機制的了解，更顯得重要，對突破治療敗血症的瓶頸將會有很大的幫助。一個完整的延腦鼻端腹外側區、腦幹脊髓路徑、及中間質外側細胞柱組合是維持基礎血管運動張力之首要條件。動脈血壓頻譜能反應延腦鼻端腹外側區的交感神經前運動神經元的活性，所產生的神經性血管運動張力訊號是透過活化位在胸、腰脊髓中間質外側細胞柱內的節前交感神經元。而兩大類的麩胺酸鹽受器 – NMDA 及non-NMDA受器在生理及敗血症狀態下，它們對產生神經性血管運動張力的相對貢獻為何，至今仍未十分清楚。我們合併生理、藥理實驗、及雙重免疫螢光染色方法去探討腦脊髓中間質外側細胞NMDA及non-NMDA受器於生理及敗血症狀態下對交感神經性血管運動張力之貢獻。

為能更精準將欲投予之藥物，直接投予到IML區域，實驗需要預先在大鼠胸脊髓蜘蛛網下腔埋置導管。因目前採用的置管方法常合併較高的手術後死亡率及傷殘率，在本研究中，我們發展一套更優良的胸脊髓蜘蛛網下腔導管置放技術。在PE-10導管一端往後2公分處黏上一粒矽膠小珠，導管內置放一條4/0的血管縫合線，縫合線的一端被摺成L-型鈎狀構造，利用L-型線端作為探針，探索到已被刺開的硬椎膜，然後導管順著縫合線滑入蜘蛛網下腔，直到矽膠小珠卡在T13脊椎椎弓板上被鑽開2 x 2公分大小的入口處。經由脊髓攝影及藥理實驗證明埋置的導管，可有效且成功的將藥物投予到胸脊髓蜘蛛網下腔。

Sprague-Dawley 雄鼠在propofol 維持麻醉狀況下，在T10-T12脊髓蜘蛛網下腔給予三個等莫爾 (equimolar) 濃度 (75，150，300 nmol) 的NMDA拮抗劑 (dizocilpine, MK801)，或non-NMDA拮抗劑 (6-cyano-7-nitroquinoxaline-2,3-dione, CNQX)。實驗結果顯示在生理狀態下，這兩種拮抗劑在同一莫爾濃度下，在相同時間點上所造成神經性血管運動張力抑制的效果是相同的。預先在胸脊髓蜘蛛網下腔給予其中一種拮抗劑，再以靜脈注射Escherichia coli 內毒素 (30 mg/kg)，所引起的低血壓、心跳過慢及血管運動張力下降等效應都比單純內毒素引起的效應來得强勁，並加速動物的死亡。我們的結果更顯示150 nmol的CNQX在敗血症時所產生的效應與300 nmol的MK801所產生的效應是相同的。利用雷射掃描共軛焦顯微鏡觀察節前交感神經元，發現NMDA受器的NR1次單元其免疫反應被強化的時段，剛好與敗血症進入交感神經興奮期吻合；但non-NMDA受器的GluR1次單元之免疫反應，在整個敗血症過程中都沒有改變。

具有節前交感神經元的定位及辨認能力，對實驗結果的正確詮釋是攸關重要，在進行節前交感神經元上麩胺酸鹽受器表現觀察前，應對節前交感神經元在中間質外側細胞柱內的位置、分佈、及細胞形態作充份了解。我們利用低電流刺激延腦鼻端腹外側區，誘發節前交感神經元表現c-fos蛋白質，再利用免疫組織學觀察帶有c-fos蛋白質免疫反應產物的細胞，並觀察其形態及分佈。c-fos蛋白質陽性細胞祇在中間質外側細胞柱區域發現。

綜合相關結果，本論文研究推論胸脊髓節前交感神經元上的NMDA及non-NMDA受器在生理狀態下，對神經性血管運動張力產生的貢獻是相等的。在敗血症狀態下，胸脊髓節前交感神經元上的NMDA受器在維持神經性血管運動張力上，扮演決定性的角色。

The management of septic patients posts a professional challenge because of the reduction in systemic vascular resistance and the progressively diminished response to sympathomimetic pressor agents. The refractory hypotension remains a significant cause of morbidity and mortality in septic patients. Under physiological conditions, neurogenic vasomotor tone plays an important role in the maintenance of normal blood pressure. A better understanding of the regulatory machinery on neurogenic vasomotor tone during sepsis is therefore of vital importance. The integrity of rostral ventrolateral medulla (RVLM), bulbospinal tract, and intermediolateral cell column (IML) plays an important role in maintaining resting vasomotor tone. The vasomotor components of the systemic arterial pressure (SAP) spectrum reflect the activities of the sympathetic premotor neurons in RVLM, and the vasomotor signals are transmitted through activation of glutamate receptors on sympathetic preganglionic neurons (SPN) in IML. However, the relative contribution of the two major subtypes of glutamate receptors, NMDA and non-NMDA receptors, to the generation of neurogenic vasomotor tone under physiological conditions or during experimental endotoxemia is basically unknown. We addressed this issue by using a combination of physiological, pharmacological and double immunofluorescence approaches to delineate the relative contribution of NMDA and non-NMDA receptors on SPN to the generation of neurogenic vasomotor tone under physiological conditions and during experimental endotoxemia.

For more accurate distribution of drugs over the specific IML region, a pre-implanted catheter in the thoracic subarachnoid space is mandatory. The currently available methods for catheterization of the thoracic spinal subarachnoid space in rats have been associated with relatively high postoperative mortality and morbidity. In our study, we developed a better method of catheterization. An intrathecal catheter was fabricated with a small silicon bead at one end of a PE-10 catheter, which was cannulated with a 4/0 suture that served as a guide. Using the L-shape hook of the suture guide as an anchorage, the catheter was advanced into the subarachnoid space until the silicon bead was lodged on a drilled hole (2 x 2 mm) over the lamina proper on the T13 vertebrae. The applicability of the implanted catheter was demonstrated by myelogram and pharmacological studies.

Adult male Sprague-Dawley rats maintained under propofol anesthesia were used. Intrathecal administration of equimolar concentrations (75, 150 or 300 nmol) of a NMDA antagonist, dizocilpine (MK801) or a non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into T10-T12 spinal cord elicited a reduction in resting vasomotor tone that was comparable in time-course and in magnitude. At the same time, both glutamate receptor antagonists exacerbated mortality and potentiated the elicited hypotension, bradycardia or reduction in vasomotor tone during experimental endotoxemia induced by intravenous administration of Escherichia coli lipopolysaccharide (30 mg/kg). Results comparable to CNQX at 150 nmol were obtained only when MK801 was given at 300 nmol. Confocal microscopy further showed that augmented immunoreactivity of NR1 subunit of the NMDA receptor on IML neurons coincided with the phase of endotoxemia when vasomotor tone was augmented; the immunoreactivity GluR1 subunit of the non-NMDA receptor remained stable throughout experimental endotoxemia.

Correct localization and identification of SPN was crucial to the interpretation of our results. We thus have to be familiar with the location, morphology, and distribution of SPN in IML for accurate location of glutamate receptor expression on SPN. c-fos protein was induced in SPN through electrical stimulation to RVLM and visualized by immunohistochemical method. It was found that c-fos positive cells were not present in the spinal cord except within the IML region.

We concluded that NMDA and non-NMDA receptors on IML neurons contribute equally to the generation of resting sympathetic vasomotor tone. However, upregulation of NMDA receptors on IML neurons plays a crucial role in the maintenance of vasomotor tone during endotoxemia.

目 錄
指導教授推薦書…………………………………………………………………
口試委員會審定書………………………………………………………………
授權書………………………………………………………………………………...iii
簽署人須知…………………………………………………………………………...iv
誌謝……………………………………………………………………………………v
中文摘要……………………………………………………………………………..vii
英文摘要………………………………………………………………………………x
目錄………………………………………………………………. ………………...xiii
第一章 緒論…………………………………………………………………………1
1-1 敗血症 (Sepsis)………………………………………………..……………..1
1-1-1 敗血症的定義……………………………………………………............1
1-1-2 敗血症的病原學及病理生理學………………………………………...2
1-1-3 敗血症的治療瓶頸……………………………………………………....4
1-2 神經性血管運動張力 (Neurogenic vasomotor tone)………………………..5
1-2-1 延腦鼻端腹外側區………………………………………………………5
1-2-2 神經性血管運動張力與脊髓的關係……………………………………7
1-2-3 中間質外側細胞柱 (IML)………………………………………………7
1-2-4 節前交感神經元 (SPN)…………………………………………………8
1-2-5 RVLM與SPN之聯繫…………………………………………………..8
1-2-6 與SPN相關的其他神經傳導物質……………………………………...9
1-2-7 神經性血管運動張力與glutamate………………………………..........11
1-2-8 外圍神經對SPN的影響………………………………………….........12
1-2-9 SPN的定位……………………………………………………………13

1-3 動脈血壓頻譜分析法
(Power spectral analysis of systemic arterial pressure signal)……..............14
1-3-1 動脈血壓頻譜分析法之特點及起源……..……………………............14
1-3-2 動脈血壓頻譜分析法之原理…..…………………………………........14
1-3-3 動脈血壓頻譜的組成及其意義…..………………………………........16
1-4 VLF和LF之重要性義………………..……………………………………..17
1-4-1 VLF和LF與RVLM的關係…………………..………………………...17
1-4-2 VLF和LF的功率密度在重症病患的意義……..……………………...19
1-5 實驗性敗血症在動脈血壓頻譜分析下的特性……..……………………...19
1-6 脊髓蜘蛛網下腔給藥的重要性………………..…………………………...20
第二章 研究動機與目的………………………………………................................22
2-1 研究動機 (Rationale)…………………………………..…………………...22
2-2 研究目的…………………………………………………..………………...24
第三章 材料與方法…………………………………………………………............25
3-1 置放胸脊髓蜘蛛網下腔導管………………………..……………………...25
3-1-1 動物選擇…………………………………..……………………………25
3-1-2 導管設計…………………………………..……………………………25
3-1-3 導管置入手術…………………………..………………………………25
3-1-4 成功導管置入手術之標準…………………..…………………………27
3-1-5 比較現有置放胸脊髓蜘蛛網下腔導管的方法…..……………………27
3-1-6 脊髓X先攝影圖標………………………………..……………………28
3-2 測試從導管注入NMDA受器拮抗劑或non-NMDA受器拮抗劑
到胸脊髓蜘蛛網下腔後對動脈血壓頻譜VLF功率密度的影響…............28
3-2-1 實驗前準備……………………………………………………...……...28
3-2-2 動脈血壓頻譜分析…………………………………………...………...29
3-2-3 non-NMDA及NMDA拮抗劑對VLF的影響…..……………............29
3-2-4 統計分析………...……………………………………………………...30
3-3 節前交感神經元的定位…..…………………………………………...........30
3-3-1 動物及實驗前的準備…………...……………………………………...30
3-3-2 對RVLM作電刺激…………..………………………………………...31
3-3-3 灌流固定……………………...………………………………………...31
3-3-4 Fos-like蛋白質之免疫細胞化學染色法…..…………………………32
3-4 胸脊髓中間質外細胞柱NMDA及non-NMDA受器對交感
神經性血管運動張力之貢獻……………………………………………..33
3-4-1 實驗前的準備手術………………………………...…………………...33
3-4-2 生理狀態……………………………………………...………………………34
3-4-3 在實驗性敗血症狀態下……………………….…...…………………..34
3-5 雙重免疫螢光染色……………………………………..…………………...35
3-6 統計分析………………………………………………..…………………...36
第四章 結果…………………………………………………….……………… …..38
4-1 置放胸脊髓蜘蛛網下腔導管……………………………………..…...........38
4-1-1比較手術後產生的合併症……………………………………..….........38
4-1-2脊髓X光圖像.................………………………………..………............39
4-1-3應用胸脊髓蜘蛛網下腔導管於脊髓功能性實驗上之可行性……..….39
4-2 節前交感神經元的定位…………………………………………..………...40
4-2-1電刺激的血壓反應…………………………………………..………….40
4-2-2利用c-fos蛋白質表現特性對SPN作定位……………….……………41
4-3 胸脊髓SPN上的NMDA及non-NMDA受器對交感神經性
血管運動張力之貢獻……………………………………………………..42
4-3-1生理狀態下胸脊髓SPN上的NMDA及non-NMDA受器
對交感神經性血管運動張力之貢獻…………………………………..42
4-3-2 胸脊髓SPN上的NMDA及non-NMDA受器對實驗性敗
血症引起的死亡率之差別角色………………………………………43
4-3-3 敗血症狀態下胸脊髓SPN上的NMDA及non-NMDA受
器對神經性血管運動張力之貢獻……………………………………44
4-4 胸脊髓SPN上的NMDA及non-NMDA受器在基礎狀態下
及實驗性敗血症下的差別表現…………………………………………..45
第五章 討論……………………………………………………………..…………..47
5-1 胸脊髓蜘蛛網下腔置放導管之技術………………………………..……...47
5-2 節前交感神經元的定位………………………………………..…………...51
5-3 胸脊髓SPN上的NMDA及non-NMDA受器在不同環境下
對神經性血管運動張力的角色……………………………………..........52
第六章 結論與展望 …………………………………..………………………..60













圖表……………………………………………………………………………….… 63
表一、比較三種不同胸脊髓蜘蛛網下腔置放導管技術的後遺症…………………63
圖一、改良型蜘蛛網下腔導管構造。矽膠珠黏在導管端後兩公分處，
導管兩端各伸出一公分長的縫合線，在矽膠珠端的縫合線被摺
成一個L-型結構..............................................................................................64
圖二、置放胸脊髓蜘蛛網下腔導管之實品圖。 a. 分離脊椎旁肌肉後
鑽孔後的T13椎弓板 (箭頭)。b. 導管經縫合線引渡進入蜘蛛
網下腔 (箭頭)……………………………………………………………......65
圖三、置放胸脊髓蜘蛛網下腔導管過程之示意圖。 a. 胸脊椎的背面
圖，顯示導管進入蜘蛛網下腔的入口。 b至f. T13椎弓板鑽孔
的縱切面圖，顯示出各重要步驟，包括導引導管進入蜘蛛網下
腔、導管留置、及導管固定…………………………………………………..66
圖四、大白鼠頭部背面圖，顯示RVLM的座標位置，頂骨與枕骨交
會點 (lambda)，往後退3.2 – 3.8 mm，左右離中線1.6 – 1.8 mm，
即A及A’兩點，垂直往下約8 mm可達RVLM …………………………….67
圖五、脊髓X-光圖像顯示顯影劑在蜘蛛網下腔之分佈。 a. 未注入
顯影劑。 b至e. 連續四次注入顯影劑，每次相隔5分鐘，
分別注入10， 20， 20，及 20 L顯影劑。直線標示乃顯影
劑的分佈範圍，箭頭表示在蜘蛛網下腔的導管末端………………………68
圖六、蜘蛛網下腔給予aCSF、CNQX (上圖)、或MK801(下圖)對動脈
血壓頻譜的VLF功率密度之影響，數值為給試劑後三十分鐘內
VLF功率密度之總和，以平均數 ± SEM表示，每一組包含五隻
動物。利用Student-Newman-Keuls 多區間檢定各組的差異；
*P ＜ 0.05表示用藥組與相對應控制組比較達到統計差異……………...69
圖七、電刺激RVLM引起血壓及心跳的改變，箭頭所指為電刺激
開始，刺激持續三分鐘，休息七分鐘，電流強度為50 A………………70
圖八、低倍數顯微鏡下胸脊髓橫切面代表圖，顯示RVLM經過電
刺激後，只有在特定區域的細胞才有c-fos蛋白質的表現。
節頭所指黑色小點為c-fos蛋白質免疫反應產物。尺規長度
為30 m……………………………………………………………………...71
圖九、中、高倍數顯微鏡下胸脊髓橫切面代表圖，顯示RVLM經過
電刺激後，IML內一些細胞有c-fos蛋白質的表現。 節頭所指黑
點為c-fos蛋白質免疫反應產物且局限在細胞核內。尺規長度分
別為30 m及10 m…………………………………………………………72
圖十、低倍數顯微鏡下的胸脊髓縱切面代表圖，顯示RVLM經過電刺
激後，在IML細胞產生c-fos蛋白質，箭頭所指均為帶有c-fos
蛋白質的免疫反應產物。尺規長度為30 m……………………………….73
圖十一、在T10-T12脊髓蜘蛛網下腔投與aCSF、MK801、或CNQX
後所產生的血壓、心跳、LF或VLF功率密度變化與時間
的關係。箭頭為投藥時間。實驗數值以平均數 ± SEM表
示，每組包含了五到六隻動物。利用Scheffé 多區間檢定
比較各組在相同時間點的差異，*P ＜ 0.05表示aCSF組達
到統計差異； +P < 0.05表示MK801組(75 nmol) 或CNQX
組(75 nmol) 達到統計差異........................................................................74
圖十二、在脊髓蜘蛛網下腔分別投與aCSF、MK801、或CNQX，
再從靜脈給予生理食鹽水或LPS (30 mg/kg) 後對動物存活率
的影響。在實驗開始時，每組包含了5到6隻動物…………………… 75
圖十三、經靜脈注射LPS (30 mg/kg) 所產生的血行動力學及動脈血壓
頻譜改變的代表圖。Phases I, II, III的劃分是以VLF及LF
功率密度之改變作為依據………………………………………………..76
圖十四、在胸脊髓蜘蛛網下腔投與aCSF, MK801 或 CNQX (a箭頭)，
再從靜脈給予生理食鹽水或LPS (30 mg/kg) (b箭頭) 後所產生
的血壓、心跳、LF或VLF功率密度變化與時間的關係。實驗
數值以平均數 ± SEM差表示，每組包含了五到六隻動物。利用
Scheffé 多區間檢定各組在相同時間點的差異；*P ＜ 0.05表示
aCSF+生理食鹽水組達到統計差異； +P < 0.05表示aCSF+LPS
組達到統計差異…………………………………………………………..77
圖十五、在動物胸脊髓蜘蛛網下腔給予CNQX (150 nmol)，再從靜脈給
予LPS (30 mg/kg) 後所產生的血壓、心跳、LF及VLF功率密
度變化與時間關係的代表圖......................................................................78
圖十六、在動物胸脊髓蜘蛛網下腔給予MK801 (150 nmol)，再從靜脈給
予LPS (30 mg/kg) 後所產生的血壓、心跳、LF及VLF功率密
度變化與時間關係的代表…......................................................................79
圖十七、雷射掃描共軛焦顯微鏡下脊髓T10-T12之IML的代表圖，
顯示細胞對神經細胞特定核蛋白NeuN (紅色螢光) 呈免疫
反應，並且對NR1單元 (綠色螢光) 呈免疫反應。 a、b是
取自在麻醉下沒有LPS處理的動物。 注意當紅色螢光和綠色
螢光重疊後會產生黃色螢光。尺規長度為20 m……………………….80
圖十八、雷射掃描共軛焦顯微鏡下脊髓T10-T12右側IML的代表圖，
顯示細胞對神經細胞特定核蛋白NeuN (紅色螢光) 呈免疫反
應，並且對NR1單元 (綠色螢光) 呈免疫反應。A、B是取
自在麻醉下沒有LPS處理的動物。C、D是取自處在敗血症
第一期的動物，E、F是取自處在敗血症第二期的動物。
G、H是取自敗血症第三期的動物。 注意當紅色螢光和綠色
螢光重疊後會產生黃色螢光。尺規長度為20 m……………………….81
圖十九、雷射掃描共軛焦顯微鏡下脊髓T10-T12右側IML的代表圖，
顯示細胞對神經細胞特定核蛋白NeuN (紅色螢光) 呈免疫反
應，並且對GluR1單元 (綠色螢光) 呈免疫反應。A、B是
取自在麻醉下，且沒有LPS處理的動物；C、D是取自處在
敗血症第一期的動物，E、F是取自處在敗血症第二期的動
物；G、H是取自處敗血症第三期的動物。注意當紅色螢光
和綠色螢光重疊後會產生黃色螢光。尺規長度為20 m……………….82
參考文獻……………………………………………………………………………..83
附錄…………………………………………………………………………………102

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